This was the question Dr Lee Rubin addressed in his recent talk at King's College London. Lee Rubin is Professor of Stem Cell and Regenerative Biology at Harvard University and Director of Translational Medicine at the Harvard Stem Cell Institute. He has worked both in academia and in industry, where he made important contributions to the treatment of multiple sclerosis and invasive basal cell carcinoma.

Much of his current research effort is devoted to identifying therapeutics for orphan neural disorders such as Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS), using new kinds of stem cell-based screens. SMA is the most common genetic cause of death in young children and has recently received a great deal of attention from researchers because of its monogenic nature and seemingly straightforward path to the clinic. The disease is known to be associated with mutations in the Survival of Motor Neuron 1 (SMN1) gene that result in a severe reduction of SMN1 protein1. A small amount of SMN protein is also produced from a gene similar to SMN1 called SMN2, but the corresponding protein is truncated and unstable2,3. In people with spinal muscular atrophy, both copies of the SMN1 gene are altered or missing and little or no protein is produced from this gene. In some cases, however, individuals have three or more copies of the SMN2 gene. In those with spinal muscular atrophy, the additional copies of the SMN2 gene are associated with a milder course of the disorder indicating that they somewhat compensate for the loss of the SMN1 protein. Symptoms of spinal muscular atrophy are still evident in those patients, however, because only a small amount of the full-size SMN protein is produced from the SMN2 genes4.

While many details about SMA are not understood, data obtained from SMA patients and from SMA mouse models suggest that therapeutics that elevate SMN levels could be effective in treating this disease5. The most promising approaches for a potential SMA therapy thus involve increasing SMN2 protein levels6. Lee Rubin's group uses iPS cells derived from SMA patients to overcome difficulties with culturing motor neurons, and to avoid the need of non-disease relevant cells. So far the Rubin lab has characterized over 40 iPS lines from five SMA patients. By performing a small molecule screen, they have identified two small molecule inhibitors of GSK3 and the proteasome, respectively, which are able to increase SMN protein levels and increase motor neuron survival. Studying ES cells derived from an SMA mouse model, the Rubin lab also found that SMA ES cells give rise to motor neurons faster, but also die very rapidly, necessitating an early window of therapeutic treatment, probably already in utero.

In conclusion, the recent research from the Rubin lab has shown us that one of the great advantages of enlisting iPS cells in modelling human disease is the ability to directly investigate the disease-relevant cells, especially when they are difficult to isolate and culture, such as in the case of motor neurons.